1H-pyrido[3,4-b]indole-4-carboxamide derivatives, preparation and application thereof in therapeutics

ABSTRACT

Compounds of general formula (I) ##STR1## in which the variables are as defined in the specification, their preparation and their application in therapeutics.

The subject of the present invention is1H-pyrido[3,4-b]indole-4-carboxamide derivatives, their preparation andtheir application in therapeutics.

The compounds of the invention correspond to the general formula (I)##STR2## in which X represents a hydrogen or halogen atom or a (C₁-C₃)alkyl, (C₁ -C₃)alkoxy, trifluoromethyl or phenylmethoxy group,

R₁ represents a hydrogen atom or a (C₁ -C₃)alkyl, cyclopropyl orphenylmethyl group,

R₂ represents. either a (C₁ -C₃) alkyl group optionally substituted by amethoxy group, or a phenyl(C₁ -C₃)alkyl group optionally substituted onthe phenyl ring by a halogen atom or a methyl or methoxy group, or acyclohexylmethyl group, or a thienylmethyl group, or a pyridinylmethylgroup, or a phenyl group optionally substituted by one or more halogenatoms or a (C₁ -C₃)alkyl' or (C₁ -C₃)alkoxy group, or a pyridinyl group,or a 5-methyl-1,2-oxazolyl group, or a 5-methyl-1,3,4-thiadiazolylgroup, or a naphthyl group,

R₃ and R₄, independently of one another, each represent a hydrogen atom,a (C₁ -C₃)alkyl group, a 2-methoxyethyl group, a hydroxy(C₂ -C₄)alkylgroup, a carboxy-(C₁ -C₃)alkyl group, a (C₁ -C₃)alkoxycarbonyl(C₁-C₃)alkyl group or a phenyl(C₁ -C₃)alkyl group, or else together form,with the nitrogen atom which carries them, either a pyrrolidinyl groupoptionally substituted by a hydroxyl, ethoxy, methoxycarbonyl ormethoxymethyl group, or a piperidinyl group, or a morpholinyl group, ora 4-methylpiperazinyl group, or an azetidinyl group, or a thiazolidinylgroup, and

the bond between the carbon atoms in the 3 and 4 positions is single ordouble.

Depending on the nature of this bond, a compound according to theinvention can optionally exist in the form of a pure optical isomer orof a mixture of such isomers.

The preferred compounds are those in the general formula of which X isin the 6 position and represents a fluorine atom, R₁ represents a methylgroup, R₂ represents a phenyl group, R₃ represents a methyl group and R₄represents an ethyl group or else R₃ and R₄ form, with the nitrogen atomwhich carries them, a pyrrolidinyl ring.

The compounds of general formula (I) can be prepared by processesillustrated in the following schemes.

According to Scheme 1, the starting compound corresponds to the generalformula (II), in which X is as defined above and R₁ is as defined above;when R₁ represents hydrogen, it is possible, if desired, to carry out analkylation in order to produce a compound of general formula (II) inwhich R₁ represents a (C₁ -C₃)alkyl group. The compound of generalformula (II) is thus reacted with ethyl pyruvate of formula (III), inacidic medium, for example in the presence of gaseous hydrochloric acidin ethanol or in the presence of sulphuric acid or of boron trifluorideetherate in acetic acid, between room temperature and the refluxtemperature, in order to obtain the diester of general formula (IV).

The latter is then treated in ethanol at the reflux temperature with anamine of general formula R₂ NH₂, in which R₂ is as defined above. Anester of general formula (V) is obtained, which is converted to thecorresponding acid, of general formula (VI), by hydrolysis in basicmedium.

This acid is then converted to the primary, secondary or tertiary amideof general formula (I') by reaction with an amine of general formulaHNR₃ R₄, in which R₃ and R₄ are as defined above, either through theimidazolide obtained by reaction with N,N'-carbonyldiimidazole or##STR3## through the acid chloride.

In the compound of general formula (I') thus obtained, the bond betweenthe 3 and 4 positions is a single bond. If it is desired to prepare acompound in which this bond is a double bond, a compound of generalformula (I') is oxidized by means of2,3-dichloro-5,6-dicyanocyclohexa-2,5-diene-1,4-dione or of3,4,5,6-tetrachlorocyclohexa-3,5-diene-1,2-dione, in a solvent such astoluene or dichloromethane, between room temperature and the refluxtemperature, in order to obtain the corresponding compound, in thestructure of which the bond between the carbon atoms in the 3 and 4positions is double, which respectively has the general formula (I"):##STR4##

Finally, and if it takes place, the enantiomers can be prepared from theracemates according to any known method; thus, for example, an acid ofgeneral formula (VI) can be reacted with an optically pure chiral amine,such as α-methylbenzylamine, and the diastereoisomers can be separatedby fractional crystallization in order to arrive at an optically pureacid and then at the esters and amides which derive therefrom.

In the case of an optically pure acid of general formula (VI), thenon-racemizing coupling reaction can be carried out by any known method,for example with use of(benzotriazol-1-yloxy)tris-(pyrrolidin-1-yl)phosphoniumhexafluorophosphate.

In the case where R₂ is an aromatic ring, it is possible, if desired, toconvert the diester (IV) to the amide (VII) by heating the reactionmixture at a temperature of 100 to 200° C., in an inert solvent orwithout solvent, for example at reflux of the corresponding amine ofgeneral formula R₂ NH₂. It is then possible to convert the compound ofgeneral formula (VII) either to the ester of general formula (V), inrefluxing ethanol, in acidic medium, for example in the presence ofconcentrated hydrochloric acid, or to the acid of general formula (VI),by hydrolysis in basic medium.

The starting compounds of general formula (II), mainly with R₁ =H, aredescribed in the literature; the pyruvate of formula (III) iscommercially available.

According to Scheme 2, the starting compound corresponds to the generalformula (VIII), in which X is as defined above. This compound is reactedwith 2-ketoglutaric acid and is then treated in an acidic alcoholicmedium, for example in ethanol saturated with gaseous hydrochloric acid,at the reflux temperature, in order to obtain the diester of generalformula (IX), in which R represents a (C₁ -C₃)alkyl group. If desired,an alkylation reaction of this compound is then carried out, in order toobtain the compound of general formula (X), in which R₁ represents a (C₁-C₃)alkyl group, and then the latter is converted, in a protic solvent,for example N,N-dimethylformamide, in the presence of dimethylformamidedimethyl acetal, at the reflux temperature, in order to obtain thecompound of formula (XI). If desired, the compound of general formula(IX) can be directly converted to the compound of general formula (XI),in which R₁ represents a methyl group, under the conditions describedabove.

The compound of general formula (XI) is then treated with an amine ofgeneral formula H₂ NR₂, in which R₂ is as defined above, in a proticsolvent, for example N,N-dimethylformamide, optionally in the presenceof an acid, for example 4-methylbenzenesulphonic acid, at the refluxtemperature, in order to obtain the ester of general formula (V'). Thelatter is converted to the corresponding acid of general formula (VI')by hydrolysis in basic medium.

Finally, this acid is converted to the primary, secondary or tertiaryamide of general formula (I"), either through the imidazolide obtainedby reaction with N,N'-carbonyldiimidazole or through the acid chloride.##STR5##

The starting compounds of general formula (VIII) are commerciallyavailable. Some compounds of general formulae (IX) and (X) are describedin the literature.

According to Scheme 3, the starting material is the diester of generalformula (X), described with respect to the process of Scheme 2. Thisdiester is hydrolysed in acidic medium in order to obtain the diacid ofgeneral formula (XII), which is converted to the anhydride, for exampleby using acetyl chloride at the reflux temperature, in order to obtainthe compound of general formula (XIII). The latter is converted, byreaction with an amine of general formula HNR₃ R₄, in which R₃ and R₄are as defined above, in a chlorinated solvent, for exampledichloromethane, in order to obtain the compound of general formula(XIV), which is converted to the ester of general formula (XV), thelatter is then treated in a protic solvent, for exampleN,N-dimethylformamide, in the presence of dimethylformamide dimethylacetal, at the ref lux temperature, in order to obtain the compound ofgeneral formula (XVI), and, finally, the latter is reacted with an amineof general formula R₂ NH₂, in which R₂ is as defined above, in a proticsolvent, for example N,N-dimethylformamide, optionally in the presenceof an acid, for example 4-methylbenzenesulphonic acid, at the refluxtemperature, in order to obtain the compound of general formula (I").

Finally, if desired, a secondary amide of general formula (I"), in whichR₃ or R₄ represents hydrogen, can be converted to the tertiary amide byan alkylation reaction known to a person skilled in the art, by means ofan alkylating agent, for example an alkyl halide. Likewise, a compoundof general formula (I') or (I"), in which R₁ represents a hydrogen atom,can be converted to a compound, in the formula of which R₁ represents analkyl group, by an alkylation reaction of known type. Compounds withchemical structures analogous to that of the compounds of the inventionare described in CA 83(13) 114712c, CA 94(9) 64698g and CA 96(9) 68779y.

Some compounds of general formulae (XII), (XIII), (XIV) and (XV) aredescribed in the literature. A compound of general formula (I) in whichR₃ and/or R₄ represent a hydroxy(C₂ -C₄)alkyl group can be obtained byreaction of the corresponding acid of general formula (VI) or (VI') withan alcohol protected by a conventional protective group, followed bydeprotection.

A compound of general formula (I) in which R₃ and/or R₄ represent acarboxy(C₂ -C₄)alkyl group can be obtained by hydrolysis of acorresponding ester. A compound of general formula (I) in which Xrepresents a phenylmethoxy group can be obtained in two stages, known toa person skilled in the art, from a compound of general formula (I) inwhich X represents a methoxy group.

The following examples illustrate in detail the preparation of a fewcompounds according to the invention. The elemental microanalyses andthe IR and NMR spectra confirm the structures of the compounds obtained.

The numbers of the compounds shown between brackets in the titlescorrespond to those in the table given below.

EXAMPLE 1 (Compound No. 20)(±)-6-Fluoro-N,N,9-trimethyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamide

1.1. Ethyl 5-fluoro-1-methyl-1H-indole-2-carboxylate.

1.1.1. Ethyl 5-fluoro-1H-indole-2-carboxylate.

150 g (0.92 mol) of 4-fluorophenylhydrazine hydrochloride are added,while cooling the mixture, to a preprepared solution of 23 g (1 mol) ofsodium in 1.5 1 of methanol and the mixture is stirred at roomtemperature for 30 min.

The solution is concentrated under reduced pressure, the residue istaken up in dichloromethane and the sodium chloride is separated byfiltration. The solvent is evaporated under reduced pressure, theresidue is dissolved in 830 ml of ethanol containing 4.4 ml of aceticacid and 102 ml (0.91 mol) of ethyl pyruvate, and the mixture is heatedat reflux for 2 h.

The reaction mixture is concentrated under reduced pressure, the residueis taken up in ethyl acetate, the solution is washed with water anddried over sodium sulphate, and the solvent is evaporated under reducedpressure. 181.6 g (0.83 mol) of hydrazone are obtained. 214 g (1.12 mol)of 4-methylbenzenesulphonic acid monohydrate, in solution of 2.5 1 oftoluene, are dehydrated by heating the reaction mixture for 2 h atreflux in a Dean and Stark apparatus. 181.6 g (0.83 mol) of thehydrazone obtained above are added while cold and the mixture is heatedat reflux for 3 h.

The mixture is cooled, ethyl acetate and water are added, the organicphase is separated and dried, and the solvent is evaporated underreduced pressure. The residue is recrystallized from propan-2-ol and themother liquors are purified by chromatography on a column of silica gel,elution being carried out with dichloromethane. 144 g (0.7 mol) ofproduct are obtained, which product is used as is in the followingstage.

1.1.2. Ethyl 5-fluoro-1-methyl-1H-indole-2-carboxylate.

11.7 g (0.39 mol) of sodium hydride, as an 80% suspension in oil, arewashed with petroleum ether and then a solution of 62.1 g (0.3 mol) ofethyl 5-fluoro-1H-indole-2-carboxylate in 600 ml of dimethylformamide isadded. The mixture is stirred for 2 h at room temperature and then 24.3ml (0.39 mol) of methyl iodide, in solution in 50 ml ofdimethylformamide, are added. The mixture is stirred for 20 h at roomtemperature and is then poured onto ice-cold water. The reaction mixtureis extracted with ethyl acetate, the organic phase is washed and driedover sodium sulphate, the solvent is evaporated under reduced pre'ssureand 62.5 g (0.28 mol) of solid product are obtained, which product isused as is in the following stage.

1.2. Ethyl2-(ethoxycarbonyl)-5-fluoro-1-methyl-α-methylene-1H-indole-3-acetate.

A solution of 10.5 g (48 mmol) of ethyl5-fluoro-1-methyl-1H-indole-2-carboxylate, 18 g (155 mmol) of ethylpyruvate and 7.8 ml of concentrated sulphuric acid in 100 ml of aceticacid is stirred at room temperature for 1 h 30. The mixture isconcentrated under reduced pressure, hydrolysis is carried out withice-cold water, aqueous ammonia is added until the pH is alkaline andextraction is carried out with dichloromethane. The organic phase iswashed with water and dried over sodium sulphate, the solvent isevaporated under reduced pressure and the residue is recrystallized froma mixture of pentane and diethyl ether. 13 g (42 mmol) of solid areobtained.

Melting point: 86-88° C.

1.3. Ethyl(±)-6-fluoro-9-methyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylate.

A solution of 7 g (23 mmol) of ethyl2-(ethoxycarbonyl)-5-fluoro-1-methyl-α-methylene-1H-indole-3-acetate and15 ml (140 mmol) of benzylamine in 200 ml of ethanol is heated at refluxfor 8 h. The solvent is evaporated under reduced pressure and theresidue is taken up in dichloromethane and 1N hydrochloric acid. Theorganic phase is washed with water and is dried over sodium sulphate.The solvent is evaporated under reduced pressure and the residue ispurified by chromatography on a column of silica gel, elution beingcarried out with a mixture of dichloromethane and ethyl acetate. 7 g (18mmol) of solid product are obtained, which product is used as is in thefollowing stage.

1.4.(±)-6-Fluoro-9-methyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylicacid.

6 g (16 mmol) of ethyl(±)-6-fluoro-9-methyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylateare hydrolysed with 2.5 g of sodium hydroxide in a mixture of water andethanol, the mixture is concentrated under reduced pressure, water andacetic acid are added, extraction is carried out with ethyl acetate, theorganic phase is washed with water and dried over sodium sulphate, andthe solvent is evaporated under reduced pressure. 4 g (11 mmol) of solidare obtained, which solid is used as is in the following stage.

Melting point: 264-265° C.

1.5.(±)-6-Fluoro-N,N,9-trimethyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamide.

A solution of 4 g (11 mmol) of(±)-6-fluoro-9-methyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylicacid and 2.2 g (30 mmol) of 1,1'-carbonyldiimidazole in 200 ml oftetrahydrofuran is heated at 40° C. for 2 h. The reaction mixture iscooled and a large excess of liquefied dimethylamine is added and themixture is allowed to stir for a few hours.

The solvent is evaporated under reduced pressure, the residue is takenup in dichloromethane and water, the organic phase is separated, washedwith water and dried over sodium sulphate, the solvent is evaporatedunder reduced pressure and the residue is purified by chromatography ona column of silica gel, elution being carried out with a mixture ofdichloromethane and methanol. The product is recrystallized from ethylacetate. 1.2 g (3 mmol) of product are obtained.

Melting point: 185-186° C.

EXAMPLE 2 (Compound No. 59)6-Fluoro-N,N,9-trimethyl-1-oxo-2-(phenylmethyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxamide

A solution of 2 g (5 mmol) of(±)-6-fluoro-N,N,9-trimethyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamideand of 1.6 g (7 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in250 ml of dichloromethane is stirred for 1 h. The organic phase iswashed and dried over sodium sulphate. The solvent is evaporated underreduced pressure and the residue is purified by chromatography on acolumn of silica gel, elution being carried out with a mixture ofdichloromethane and ethyl acetate. The product is crystallized fromdiethyl ether. 1 g (2.6 mmol) of product is obtained.

Melting point: 192-193° C.

EXAMPLE 3 (Compound No. 36)6-Chloro-2-(2-methoxyethyl)-N,N,9-trimethyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamide

3.1. Ethyl 5-chloro-1-methyl-1-H-indole-2-carboxylate.

The preparation is carried out as in Example 1.1.2, from 8.95 g (40mmol) of ethyl 5-chloro-1H-indole-2-carboxylate, 1.6 g (52 mmol) ofsodium hydride, as an 80% suspension in oil, and 11.35 g (80 mmol) ofmethyl iodide. 9.5 g (40 mmol) of solid product are obtained, whichproduct is used as is in the following stage.

3.2. Ethyl5-chloro-2-(ethoxycarbonyl)-1-methyl-α-methylene-1H-indole-3-acetate.

A solution saturated with hydrochloric acid and containing 9.5 g (40mmol) of ethyl 5-chloro-1-methyl-1H-indole-2-carboxylate and 8.8 ml (80mmol) of ethyl pyruvate is heated at reflux for 4 h. The solvent isevaporated under reduced pressure, the residue is taken up in ethylacetate, which is washed to neutrality, the organic phase is dried oversodium sulphate and the solvent is evaporated under reduced pressure.The product is purified by chromatography on a column of silica gel,elution being carried out with dichloromethane. 9.6 g (32 mmol) of solidproduct are obtained, which product is used as is in the followingstage.

3.3. Ethyl(±)-6-chloro-2-(2-methoxyethyl)-9-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylate.

A solution of 9.5 g (31 mmol) of ethyl5-chloro-2-(ethoxycarbonyl)-1-methyl-α-methylene-1H-indole-3-acetate and8.1 g (93 mmol) of 2-methoxyethylamine in 20 ml of ethanol is heated atreflux for 3 h.

The solvent is evaporated under reduced pressure and the residue istaken up in ethyl acetate, which is washed with water and dried oversodium sulphate. 9.7 g (27 mmol) of solid product are obtained, whichproduct is used as is in the following stage.

3.4.(±)-6-Chloro-2-(2-methoxyethyl)-9-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylicacid.

9.6 g (26 mmol) of ethyl(±)-6-chloro-2-(2-methoxyethyl)-9-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylateare hydrolysed with a solution of 3.1 g (80 umol) of sodium hydroxide in260 ml of ethanol and 50 ml of water. The reaction mixture isconcentrated, the residue is taken up in water and the aqueous phase iswashed with ethyl acetate and acidified to pH=1 with concentratedhydrochloric acid. Extraction is carried out with ethyl acetate. Theorganic phase is washed with water and dried with sodium sulphate. Thesolvent is evaporated under reduced pressure and 8.3 g (26 mmol) ofsolid product are obtained, which product is used as is in the followingstage.

3.5.(±)-6-Chloro-2-(2-methoxyethyl)-N,N,9-trimethyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamide.

The preparation is carried out as in Example 1.5, from 8.3 g (26 mmol)of(±)-6-chloro-2-(2-methoxyethyl)-9-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylicacid and from dimethylamine. 8.6 g of product are isolated, whichproduct is recrystallized from propan-2-ol. 6.9 g (19 mmol) of productare obtained.

Melting point: 217-219° C.

EXAMPLE 4 (Compound No. 77)(+)-6-Fluoro-N,N,9-trimethyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamide

4.1.(+)-6-Fluoro-9-methyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylicacid.

A solution of 20.5 g (58 mmol) of(±)-6-fluoro-9-methyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylicacid and of 7.5 ml (58 mmol) of (R)-(+)-α-methylbenzylamine in 1000 mlof methanol is stirred. The mixture is concentrated under reducedpressure, the residue is taken up in 50 ml of ethyl acetate and 400 mlof diethyl ether, and the precipitate is separated by filtration andrecrystallized three times from propan-2-ol.

7.3 g (15 mmol) of diastereoisomer salt are isolated, which salt isredissolved in 100 ml of methanol, 16 ml of 1N hydrochloric acid and 200ml of water are added, and the precipitate is separated by filtrationand dried under reduced pressure at room temperature. 5.1 g (15 mmol) ofdextrorotatory acid are obtained.

Melting point: 264-269° C. [α]_(D) ²⁰ =+41.6° (c=0.5, CH₃ OH) ee>99%(HPLC).

4.2.(+)-6-Fluoro-N,N,9-trimethyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamide.

A solution of 0.5 g (1.3 mmol) of(+)-6-fluoro-9-methyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylicacid, 0.11 g (1.3 mmol) of dimethylamine hydrochloride, dried beforehandunder reduced pressure, and 0.68 g (13 mmol) of(benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphatein 10 ml of dichloromethane, passed beforehand through an aluminacolumn, is cooled to -30° C. and 0.68 ml (3.9 mmol) ofN,N-di(1-methylethyl)ethylamine, in solution in 5 ml of dichloromethane,is added dropwise. The mixture is stirred for 6 h at between -30° C. and-20° C., hydrolysis is carried out with 10 ml of 5% aqueous potassiumhydrogensulphate solution, the mixture is extracted withdichloromethane, the organic phase is washed and dried, the solvent isevaporated under reduced pressure, the residue is purified bychromatography on a column of silica gel, elution being carried out witha mixture of dichloromethane and ethyl acetate, and the product obtainedis recrystallized from propan-2-ol. 0.37 g (1 mmol) of dextrorotatoryamide is obtained.

Melting point: 199-202° C. [α]_(D) ²⁰ =+6.3° (c 1, CHCl₃) ee>94% (HPLC).

EXAMPLE 5 (Compound No. 76)(-)-6-Fluoro-N,N,9-trimethyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamide

5.1.(-)-6-Fluoro-9-methyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylicacid.

The solvent from the various mother liquors from the recrystallizationof the diastereoisomer salt of Example 4.1 is evaporated under reducedpressure, water and concentrated hydrochloric acid are added, and theprecipitate is separated by filtration and dried under reduced pressureat room temperature. 13.6 g (38 mmol) of impure laevorotatory acid areobtained, to which are added 250 ml of methanol and 4.97 ml (38 mmol) of(S)-(-)-α-methylbenzylamine.

The mixture is stirred and concentrated under reduced pressure and theprecipitate is collected by filtration and recrystallized three timesfrom propan-2-ol. 7 g (15 mmol) of diastereoisomer salt are obtained,which salt is redissolved in the minimum amount of methanol, 15 ml of 1Nhydrochloric acid are added and the volume of the solution is doubledwith water. The precipitate is separated by filtration, washed withwater, superficially dried, and dried at room temperature under reducedpressure. 5 g (14 mmol) of laevorotatory acid are obtained.

Melting point: 264-269° C. [α]_(D) ²⁰ =-42.2° (c=0.5, CH₃ OH) ee>99%(HPLC).

5.2.(-)-6-Fluoro-N,N,9-trimethyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamide.

By carrying out the preparation as described in Example 4.2, from(-)-6-fluoro-9-methyl-1-oxo-2-(phenylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylicacid and from dimethylamine, 0.3 g (0.8 mmol) of laevorotatory amide isobtained after final recrystallization from ethyl acetate.

Melting point: 204-205° C. [α]_(D) ²⁰ =-7.5° (c=1, CHCl₃) ee>98% (HPLC).

EXAMPLE 6 (Compound No. 101) 6-Fluoro-N,N,9-trimethyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxamide

6.1. Ethyl 2-(ethoxycarbonyl)-5-fluoro-α-methylene-1H-indole-3-acetate.

A solution of 37.2 g (180 mmol) of ethyl5-fluoro-1H-indole-2-carboxylate, 25.8 g (222 mmol) of ethyl pyruvateand 31 ml of concentrated sulphuric acid in 400 ml of acetic acid isstirred for 20 h.

The solvent is evaporated under reduced pressure, the residue is takenup in water and ethyl acetate, the organic phase is separated, washedwith a dilute aqueous ammonia solution and then with a saturated aqueoussodium chloride solution and dried over sodium sulphate, and the solventis evaporated under reduced pressure.

37.1 g (122 mmol) of solid product are obtained, which product is usedas is in the following stage.

6.2.6-Fluoro-1-oxo-2-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylicacid.

A mixture of 25 g (82 mmol) of ethyl2-(ethoxycarbonyl)-5-fluoro-α-methylene-1H-indole-3-acetate and 31.8 g(342 mmol) of aniline is heated at reflux for 17 h. A dilutehydrochloric acid solution and ethyl acetate are added, the organicphase is separated, washed with water and dried with sodium sulphate,and the solvent is evaporated under reduced pressure. 30 g of residueare obtained, which residue is hydrolysed with a solution of 43 ml of30% sodium hydroxide in 400 ml of ethanol at reflux for 1 h.

The mixture is concentrated under reduced pressure, water is added, themixture is washed with ethyl acetate and dichloromethane, the aqueousphase is acidified with concentrated hydrochloric acid, and theprecipitate is collected by filtration and dried under reduced pressure.

18.5 g (57 mmol) of solid compound are obtained, which compound is usedas is in the following stage.

6.3.6-Fluoro-N,N,9-trimethyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxamide.

5 g (15 mmol) of6-fluoro-1-oxo-2-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylicacid in 40 ml of thionyl chloride are heated at reflux for 1 h. Thesolvent is evaporated under reduced pressure, the residue is taken up indichloromethane, a large excess of liquefied dimethylamine is added, themixture is stirred for a few hours, water is added, and the precipitateis separated by filtration and dried under reduced pressure.

3.4 g (9 mmol) of compound are obtained.

2.5 g thereof are dissolved in 50 ml of dimethyl sulphoxide, 0.6 g ofpowdered potassium hydroxide and 1.2 ml of iodomethane are added, andthe mixture is stirred for 5 h at 50° C. and then for 20 h at roomtemperature.

Dilute hydrochloric acid is added, extraction is carried out with ethylacetate, the organic phase is dried over sodium sulphate, the solvent isevaporated under reduced pressure and the residue is purified bychromatography on a column of silica gel, elution being carried out witha mixture of cyclohexane and ethyl acetate.

2.2 g of a mixture containing6-fluoro-N,N,9-trimethyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxamideand6-fluoro-N,N,9-trimethyl-1-oxo-2-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamideare obtained.

This mixture is stirred with 1 g of2,3-dichloro-5,6-dicyano-1,4-benzoquinone for 20 h and is washed with asaturated aqueous sodium hydrogencarbonate solution, the organic phaseis separated and dried over sodium sulphate, the solvent is evaporatedunder reduced pressure, the residue is purified by chromatography on acolumn of silica gel, elution being carried out with a mixture ofcyclohexane and ethyl acetate, and the product is recrystallized fromethyl acetate. 0.5 g (1.5 mmol) of compound is obtained.

Melting point: 195-197° C.

EXAMPLE 7 (Compound No. 97)N,N,9-Trimethyl-1-oxo-2-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamide

7.1. Ethyl 2-(ethoxycarbonyl)-α-methylene-1H-indole-3-acetate

An ethanol solution saturated with gaseous hydrochloric acid containing39.1 g (207 mmol) of ethyl 1H-indole-2-carboxylate and 45.3 ml (410umol) of ethyl pyruvate is brought to approximately 60° C. for 3 h. Themixture is concentrated under reduced pressure and the residue is takenup in diethyl ether. The organic phase is washed with water and driedover sodium sulphate. The solvent is evaporated under reduced pressureand the residue is crystallized from cyclohexane. 45.4 g (158 mmol) ofsolid product are obtained, which product is used as is in the followingstage.

7.2.1-Oxo-N,2-diphenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamide.

A mixture of 32 g (111 mmol) of ethyl2-(ethoxycarbonyl)-α-methylene-1H-indole-3-acetate and of 47.5 g (511mmol) of aniline is heated at reflux for 13 h. Dichloromethane is addedand the organic phase is washed with 1N hydrochloric acid. It is driedover sodium oulphate and the solvent is evaporated under reducedpressure. 38.8 g of impure product are obtained, which product is usedas is in the following stage.

7.3. Ethyl1-oxo-2-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylate.

A solution of 38.8 g of impure1-oxo-N,2-diphenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamidein a mixture of ethanol, water and 37% hydrochloric acid is heated atreflux for 8 h.

The reaction mixture is neutralized with concentrated sodium hydroxideand extraction is carried out with ethyl acetate. The organic phase isdried over sodium sulphate and evaporated under reduced pressure. Theresidue is purified by chromatography on a column of silica gel, elutionbeing carried out with a mixture of dichloromethane and ethyl acetate.22.6 g (68 mmol) of product are obtained, which product is used as is inthe following stage.

7.4.1-Oxo-2-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylicacid.

22.6 g (68 mmol) of ethyl1-oxo-2-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylateare hydrolysed with 200 ml of 1N sodium hydroxide in 500 ml of methanol.The reaction mixture is acidified with 1N hydrochloric acid and theprecipitate is filtered off. It is dried under reduced pressure. 18.1 g(59 mmol) of solid product are obtained, which product is used as is inthe following stage.

7.5.N,N-Dimethyl-1-oxo-2-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamide.

A solution of 10 g (33 mmol) of 1-oxo-2-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxylic acid in 30 ml ofthionyl chloride is heated at reflux for 4 h. The solvent is evaporatedunder reduced pressure, the residue is taken up in dichloromethane and alarge excess of liquefied dimethylamine is added. The mixture is stirredfor several hours and the solvent is evaporated under reduced pressure.Water and ethyl acetate are added.

The precipitate is filtered off and dried under reduced pressure. 8.2 gof impure product are obtained, which product is used as is in thefollowing stage.

7.6.N,N,9-Trimethyl-1-oxo-2-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamide

A mixture of 1.3 g (23 mmol) of powdered potassium hydroxide and of 6 gof impureN,N-dimethyl-1-oxo-2-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-4-carboxamidein 60 ml of dimethyl sulphoxide is heated at 40° C. for 30 min. 2.5 ml(40 mmol) of iodomethane are added and the reaction mixture is stirredfor 5 h at room temperature.

Water and dichloromethane are then added. The organic phase is driedover sodium sulphate and evaporated under reduced pressure. The residueis purified by chromatography on a column of silica gel, elution beingcarried out with a mixture of dichloromethane and ethyl acetate. Theproduct is recrystallized from ethyl acetate. 1.9 g (5.5 mmol) ofproduct are obtained.

Melting point: 196-197° C.

EXAMPLE 8 (Compound No. 123)N-Ethyl-6-fluoro-N,9-dimethyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxamide

8.1. Ethyl 2-(ethoxycarbonyl)-5-fluoro-1H-indole-3-acetate

A solution of 7.4 g (185 mmol) of sodium hydroxide in 75 ml of water isadded to a solution of 30 g (185 mmol) of 4-fluorophenylhydrazinehydrochloride in 300 ml of water, the mixture is stirred for 15 min andthen a solution of 29 g (198 mmol) of ketoglutaric acid in 60 ml ofwater is added. The reaction mixture is stirred at room temperature for3 h and is extracted with ethyl acetate, and the organic phase is washedwith water, dried over sodium sulphate and evaporated under reducedpressure. 42 g (144 mmol) of product are obtained, which product isdissolved in 420 ml of ethanol saturated with gaseous hydrochloric acidand heated at reflux for 4 h.

The reaction mixture is concentrated under reduced pressure, the residueis taken up in ethyl acetate, and the organic phase is washed withnormal sodium hydroxide and then with water, dried over magnesiumsulphate and evaporated under reduced pressure. 42 g (143 mmol) of solidproduct are obtained, which product is used as is in the followingstage.

8.2. Ethyl 2-(ethoxycarbonyl)-5-fluoro-1-methyl-1H-indole-3-acetate.

A solution of 7.36 g (184 mmol) of 60% sodium hydride, washed beforehandwith petroleum ether, and 45 g (153 mmol) of ethyl2-(ethoxycarbonyl)-5-fluoro-1H-indole-3-acetate in 450 ml ofN,N-dimethylformamide is stirred for 2 h at room temperature and then asolution of 19 ml (306 mmol) of iodomethane in 100 ml ofN,N-dimdthylformamide is added. After stirring for 20 h, the reactionmixture is poured onto ice-cold water, extraction is carried out withdiethyl ether, the organic phase is washed with water and dried overmagnesium oulphate, and the solvent is evaporated under reducedpressure. 44.3 g (144 mmol) of product are obtained, which product isused as is in the following stage.

8.3. Ethylα-(dimethylaminomethylidene)-2-(ethoxycarbonyl)-5-fluoro-1-methyl-1H-indole-3-acetate.

A solution of 44.3 g (144 mmol) of ethyl2-(ethoxycarbonyl)-5-fluoro-1-methyl-1H-indole-3-acetate and 57.4 ml ofdimethylformamide dimethyl acetal in 450 ml of N,N-dimethylformamide isheated at reflux for 50 h. The solvent is evaporated under reducedpressure and the residue is taken up in diethyl ether. The insolublematerial is removed by filtration and the solvent is concentrated underreduced pressure. 49.3 g (136 mmol) of solid product are obtained, whichproduct is used as is in the following stage.

8.4. Ethyl6-fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate.

A solution of 16.3 g (45 mmol) of ethylα-(dimethylaminomethylidene)-2-(ethoxycarbonyl)-5-fluoro-1-methyl-1H-indole-3-acetate,4.64 ml (50 mmol) of aniline and 1.6 g (8 mmol) of4-methylbenzene-sulphonic acid monohydrate in 160 ml ofN,N-dimethylformamide is heated at reflux for 24 h. 3.3 g (31 mmol) ofsodium carbonate are added in small portions and reflux is continued for2 h.

The solution is cooled and poured onto ice-cold water. Extraction iscarried out with ethyl acetate and the organic phase is washed withwater, dried over magnesium sulphate and evaporated under reducedpressure. The residue is purified by chromatography on a column ofsilica gel, elution being carried out with a mixture of dichloromethaneand ethyl acetate. 10.9 g (30 mmol) of product are obtained, whichproduct is used as is in the following stage.

8.5.6-Fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylicacid.

A solution of 22.8 g (65 mmol) of ethyl6-fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylateand of 7.46 g (186 mmol) of sodium hydroxide in a mixture of 1 1 ofethanol and 100 ml of water is heated at reflux for 3 h. The mixture isconcentrated under reduced pressure, the residue is taken up in waterand the aqueous phase is washed with ethyl acetate. Acidification iscarried out with concentrated hydrochloric acid to pH=1 and the productis filtered off, which product is rinsed several times with water. It isdried under reduced pressure. 20.4 g (64 mmol) of solid compound areobtained, which compound is used as is in the following stage.

8.6.6-Fluoro-N,9-dimethyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxamide.

A solution of 5 g (15.6 mmol) of6-fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]-indole-4-carboxylicacid and of 4.8 g (30 mmol) of N,N'-carbonyldiimidazole in 100 ml ofN,N-dimethylformamide is stirred at 60° C. for 4 h. A large excess ofliquefied methylamine is added at room temperature and the reactionmixture is stirred for 20 h. The solution is poured onto ice-cold waterand the precipitate is collected by filtration, washed with a saturatedsodium hydrogencarbonate solution, with water and then with ethylacetate, and dried under reduced pressure. 3.5 g of crude product areisolated. The filtrates are combined and extracted with dichloromethane.The organic phase is washed with a sodium hydrogencarbonate solution andthen with water and dried over magnesium sulphate, and the solvent isevaporated under reduced pressure. 1.5 g of additional product areisolated. The two batches are combined and purified by chromatography ona column of silica gel, elution being carried out with a mixture ofdichloromethane and ethyl acetate. 4.7 g (13.5 mmol) of solid productare obtained.

8.7.N-Ethyl-6-fluoro-N,9-dimethyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxamide.

A solution of 2.5 g (7.1 zmol) of6-fluoro-N,9-dimethyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxamideand of 0.36 g (9 mmol) of 60% sodium hydride, washed beforehand withpetroleum ether, is stirred for 3 h at 50° C. 1.67 ml (21 mmol) ofiodoethane are added, stirring is maintained for 20 h, and the solutionis poured onto ice-cold water and extracted with ethyl acetate. Theorganic phase is washed with water, dried over magnesium sulphate andevaporated under reduced pressure. The residue is purified bychromatography on silica, the elution being carried out with a mixtureof dichloromethane and ethyl acetate. The product is recrystallized frompropan-2-ol.

2.3 g of solid are obtained.

Melting point: 181-182° C.

EXAMPLE 9 (Compound No. 98)6-Fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-ylcarbonyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one

A solution of 3.2 g (10 mmol) of6-fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylicacid and of 3.2 g (20 mmol) of N,N'-carbonyldiimidazole in 65 ml ofN,N-dimethylformamide is stirred for 4 h at 60° C. 2.5 ml (30 zmol) ofpyrrolidine are added at room temperature and the reaction mixture isstirred for 20 h.

The solution is poured onto ice-cold water and extracted with ethylacetate. The organic phase is washed with water and dried over magnesiumsulphate, and the solvent is evaporated under reduced pressure. Theresidue is purified by chromatography on a column of silica gel, elutionbeing carried out with a mixture of dichloromethane and ethyl acetate.The product is recrystallized from propan-2-ol.

3 g (7.7 mmol) of solid are obtained.

Melting point: 203-205° C.

EXAMPLE 10 (Compound No. 122)6-Fluoro-N,N,9-trimethyl-1-oxo-2-(pyridin-2-yl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxamide

10.1. Methyl6-fluoro-9-methyl-1-oxo-2-(pyridin-2-yl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate.

A mixture of 4.1 g (12.2 mmol) of methylα-(dimethylaminomethylidene)-5-fluoro-2-(methoxycarbonyl)-1-methyl-1H-indole-3-acetateand of 1.73 g (18.4 mmol) of 2-aminopyridine is heated at 180° C. for 30min. 7 ml of N,N-dimethylformamide are added and heating is continuedfor 4 h.

The reaction mixture is cooled and poured onto a mixture of water andethyl acetate, and the insoluble material is collected by filtration anddried under reduced pressure. 1.8 g (5.1 mmol) of solid are obtained,which solid is used as is in the following stage.

10.2.6-Fluoro-9-methyl-1-oxo-2-(pyridin-2-yl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylicacid.

A solution of 3.3 g (9.4 mmol) of methyl6-fluoro-9-methyl-1-oxo-2-(pyridin-2-yl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylatein a mixture of 100 ml of ethanol and of 28 ml of 1N sodium hydroxide isheated at reflux for 4 h. The mixture is concentrated under reducedpressure, water is added, acidification is carried out with concentratedhydrochloric acid and the precipitate is collected by filtration. It iswashed with water and dried under reduced pressure. 2.8 g (8.3 mmol) ofsolid product are obtained, which product is used as is in the followingstage.

10.3.6-Fluoro-N,N,9-trimethyl-1-oxo-2-(pyridin-2-yl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxamide.

A solution of 2.5 g (7.4 mmol) of6-fluoro-9-methyl-1-oxo-2-(pyridin-2-yl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylicacid and of 2.4 g (14.8 mmol) of N,N'-carbonyldiimidazole in 65 ml ofN,N-dimethylformamide is stirred for 4 h. The reaction mixture is cooledand a large excess of liquefied dimethylamine is added. The mixture isstirred for 48 h at room temperature, poured into water and extractedwith ethyl acetate. The organic phase is washed with water and driedover magnesium sulphate, and the solvent is evaporated under reducedpressure. The residue is purified by chromatography on a column ofsilica gel, elution being carried out with a mixture of dichloromethaneand ethyl acetate. The product is recrystallized from ethyl acetate.

1.6 g (4.4 mmol) of solid are obtained.

Melting point: 220-221° C.

EXAMPLE 11 (Compound No. 125)6-Fluoro-9-methyl-2-(5-methyl-1,3,4-thiadiazol-2-yl)-4-(pyrrolidin-1-ylcarbonyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one

11.1. 2-Carboxy-5-fluoro-1H-indole-3-acetic acid.

A solution of 26.5 g (103 mmol) of ethyl2-(ethoxycarbonyl)-5-fluoro-1H-indole-3-acetate and 24 g of sodiumhydroxide in a mixture of 530 ml of ethanol and of 100 ml of water isheated at reflux. The mixture is concentrated under reduced pressure,water is added, and the aqueous phase is washed with ethyl acetate andacidified with concentrated hydrochloric acid. The precipitate isfiltered off, rinsed with water and dried under reduced pressure. 23.4 g(98.7 mmol) of product are obtained, which product is used as is in thefollowing stage.

11.2. 6-Fluoro-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1,3-dione.

A solution of 4.7 g (19.8 mmol) of 2-carboxy-5-fluoro-1H-indole-3-aceticacid in 94 ml of acetyl chloride is heated at reflux for 5 h. Themixture is concentrated under reduced pressure, toluene is added and thesolvents are evaporated under reduced pressure. 4.5 g of solid productare obtained, which product is used as in the following stage.

11.3. 5-Fluoro-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-indole-2-carboxylicacid.

A solution of 4.4 g (20 mmol) of6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole-1,3-dione and of 8.3 ml(100 mmol) of pyrrolidine in 100 ml of dichloromethane is stirred for 24h at room temperature. The mixture is concentrated under reducedpressure, water is added and the aqueous phase is washed with ethylacetate. Acidification is carried out with concentrated hydrochloricacid and ethyl acetate is added. The precipitate is collected byfiltration, washed with water and dried under reduced pressure. 5 g(17.2 mmol) of solid product are obtained, which product is used as isin the following stage.

11.4. Methyl5-fluoro-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-indole-2-carboxylate.

3.8 ml (51 mmol) of thionyl chloride are added dropwise to a solution of5 g (17.2 mmol) of5-fluoro-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-indole-2-carboxylic acidin 50 ml of methanol cooled in an ice bath, and then the mixture isheated at reflux for 3 h.

The mixture is concentrated under reduced pressure, water anddichloromethane are added, and the organic phase is washed with water,dried over magnesium sulphate and evaporated under reduced pressure. 4.5g (14 mmol) df product are obtained, which product is used as is in thefollowing stage.

11.5. Methyl3-(1-dimethylaminomethylidene-2-oxo-2-(pyrrolidin-1-yl)ethyl)-5-fluoro-1-methyl-1H-indole-2-carboxylate.

A solution of 3.4 g of methyl 5-fluoro-3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-indole-2-carboxylate and 4.66 ml (35 mmol) ofdimethylformamide dimethyl acetal in 34 ml of N,N-dimethylformamide isheated at reflux for 30 h. The mixture is concentrated under reducedpressure, xylene is added and the solvents are evaporated under reducedpressure. 4 g of residue are obtained, which residue containsapproximately 50% of the desired product (according to the protonmagnetic resonance spectrum) and is used as is in the following stage.

11.6.6-Fluoro-9-methyl-2-(5-methyl-1,3,4-thia-diazol-2-yl)-4-(pyrrolidin-1-ylcarbonyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one.

A solution of 4 g of the residue obtained in the preceding stage and1.04 g (5.5 mmol) of 4-methylbenzenesulphonic acid monohydrate in 40 mlof N,N-dimethylformamide is stirred for 15 min. 0.65 g (6.4 mmol) of2-amino-5-methyl-1,3,4-thiadiazole is added and the mixture is heated atreflux for 24 h.

The mixture is poured into water and ethyl acetate. The precipitate iscollected by filtration, washed with water, dried under reduced pressureand recrystallized from N,N-dimethylformamide. 1 g (2.4 mmol) of productis obtained.

Melting point: 299-301° C.

The chemical structures and the physical properties of a few compoundsaccording to the invention are illustrated in the following table.

                                      TABLE                                       __________________________________________________________________________                                 (I)                                               ##STR6##                                                                     No.                                                                              X    R.sub.1                                                                           R.sub.2 NR.sub.3 R.sub.4                                                                       3 ˜ 4                                                                      M.p. (° C.)                            __________________________________________________________________________    1  H    Me  Pr      NHMe     /  150-152                                       2  H    Me  Pr      NMe.sub.2                                                                              /  142-144                                       3  H    Pr  Pr      NMe.sub.2                                                                              /  125-126                                       4  H    Me  PhCH.sub.2                                                                            NEt.sub.2                                                                              /  107-109                                       5  H    Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  162-163                                       6  H    Pr  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  178-180                                       7  H    Me  4-MeO--PhCH.sub.2                                                                     NMe.sub.2                                                                              /  149-150                                       8  H    Me  4-F--PhCH.sub.2                                                                       NMe.sub.2                                                                              /  174                                           9  H    Me  PhCH.sub.2 CH.sub.2                                                                   NMe.sub.2                                                                              /  138-139                                       10 H    Me  4-Cl--PhCH.sub.2                                                                      NMe.sub.2                                                                              /  168-170                                       11 H    Et  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  172-174                                       12 H    Me  2-MeO--PhCH.sub.2                                                                     NMe.sub.2                                                                              /  162-163                                       13 H    Me  3-MeO--PhCH.sub.2                                                                     NMe.sub.2                                                                              /  139-140                                       14 H    Me  2-Me--PhCH.sub.2                                                                      NMe.sub.2                                                                              /  154-156                                       15 H    Me  3-Me--PhCH.sub.2                                                                      NMe.sub.2                                                                              /  137-139                                       16 H    Et  4-MeO--PhCH.sub.2                                                                     NMe.sub.2                                                                              /  149-150                                       17 H    Me  4-Me--PhCH.sub.2                                                                      NMe.sub.2                                                                              /  153-155                                       18 H    Me  Ph(CH.sub.2).sub.3                                                                    NMe.sub.2                                                                              /  118-120                                       19 5-F  Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  195-196                                       20 6-F  Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  185-186                                       21 7-F  Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  195-196                                       22 8-F  Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  188-190                                       23 6-MeO                                                                              Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  181-182                                       24 7-MeO                                                                              Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  208-210                                       25 6-Cl Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  208-210                                       26 7-Cl Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  209-210                                       27 8-Cl Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  218-219                                       28 6-Me Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  209-210                                       29 7-Me Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  203-205                                       30 8-Me Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  204-205                                       31 6 F  Me  PhCH.sub.2                                                                            NEt.sub.2                                                                              /  120-121                                       32 6 F  Me  PhCH.sub.2                                                                            NPr.sub.2                                                                              /  156-157                                       33 6-F  Et  2-MeO--PhCH.sub.2                                                                     NMe.sub.2                                                                              /  136 137                                       34 6-F  Me  PhCH.sub.2                                                                            NHMe     /  205-206                                       35 6-F  Et  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  206-207                                       36 6-Cl Me  MeO(CH.sub.2).sub.2                                                                   NMe.sub.2                                                                              /  217-219                                       37 6-F  Me  PhCH.sub.2                                                                            NH.sub.2 /  259-260                                       38 6-F  Me  2-Pyridyl-CH.sub.2                                                                    NMe.sub.2                                                                              /  186-189                                       39 6-F  Me  2-Thienyl-CH.sub.2                                                                    NMe.sub.2                                                                              /  191-193                                       40 6-F  Me  3-Pyridyl-CH.sub.2                                                                    NMe.sub.2                                                                              /  200-202                                       41 6-F  Me  C.sub.6 H.sub.11 CH.sub.2                                                             NMe.sub.2                                                                              /  209-211                                       42 6-F  Me  PhCH.sub.2                                                                            Piperid  /  205 206                                       43 6-F  Me  PhCH.sub.2                                                                            Pyrrolid /  228-229                                       44 H    Pr  Pr      NMe.sub.2                                                                              // 107-108                                       45 H    Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              // 130-131                                       46 H    Pr  PhCH.sub.2                                                                            NMe.sub.2                                                                              // 160-162                                       47 H    Me  4-MeO--PhCH.sub.2                                                                     NMe.sub.2                                                                              //  98-100                                       48 H    Me  4-F--PhCH.sub.2                                                                       NMe.sub.2                                                                              // 105-106                                       49 H    Me  4-Cl--PhCH.sub.2                                                                      NMe.sub.2                                                                              // 103-104                                       50 H    Et  PhCH.sub.2                                                                            NMe.sub.2                                                                              // 168 170                                       51 H    Me  2-MeO--PhCH.sub.2                                                                     NMe.sub.2                                                                              // 171-173                                       52 H    Me  3-MeO--PhCH.sub.2                                                                     NMe.sub.2                                                                              // 168-170                                       53 H    Me  3-Me--PhCH.sub.2                                                                      NMe.sub.2                                                                              // 117-118                                       54 H    Et  4-MeO--PhCH.sub.2                                                                     NMe.sub.2                                                                              // 127-128                                       55 H    Me  2-Me--PhCH.sub.2                                                                      NMe.sub.2                                                                              // 157-158                                       56 H    Me  4-Me--PhCH.sub.2                                                                      NMe.sub.2                                                                              //  98-100                                       57 H    Me  Ph(CH.sub.2).sub.3                                                                    NMe.sub.2                                                                              // 107-109                                       58 5-F  Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              // 168-170                                       59 6 F  Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              // 192-193                                       60 7-F  Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              // 142-144                                       61 8-F  Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              // 190-192                                       62 6-MeO                                                                              Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              // 178-180                                       63 7-MeO                                                                              Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              // 155-156                                       64 6-Cl Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              // 200-202                                       65 7-Cl Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              // 183-184                                       66 6-Me Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              // 158-160                                       67 7-Me Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              // 154 156                                       68 8-Me Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              // 168-169                                       69 6-F  Et  PhCH.sub.2                                                                            NMe.sub.2                                                                              // 216-217                                       70 6-Cl Me  MeO--(CH.sub.2).sub.2                                                                 NMe.sub.2                                                                              // 179-180                                       71 6-F  Me  2-Pyridyl-CH.sub.2                                                                    NMe.sub.2                                                                              // 221-223                                       72 6-F  Me  2-Thienyl-CH.sub.2                                                                    NMe.sub.2                                                                              // 164-165                                       73 6-F  Me  C.sub.6 H.sub.11 CH.sub.2                                                             NMe.sub.2                                                                              // 170-172                                       74 6-F  Et  2-MeO--PhCH.sub.2                                                                     NMe.sub.2                                                                              // 199-200                                       75 6-F  Me  3-Pyridyl-CH.sub.2                                                                    NMe.sub.2                                                                              // 172-175                                       76 6-F  Me  PhCH.sub.2                                                                            NMe      /  204 205                                       77 6-F  Me  PhCH.sub.2                                                                            NMe.sub.2                                                                              /  199-202                                       78 H    H   Pr      NHMe     /  215-217                                       79 H    H   Pr      NMe.sub.2                                                                              /  202-204                                       80 H    H   Pr      NH.sub.2 /  220-222                                       81 H    H   Pr      NHCH.sub.2 Ph                                                                          /  228-230                                       82 H    H   Pr      NMe.sub.2                                                                              // 244-247                                       83 H    H   Ph      NMe.sub.2                                                                              // 292-294                                       84 6-F  H   PhCH.sub.2                                                                            NMe.sub.2                                                                              // 298 301                                       85 6-F  H   PhCH.sub.2                                                                            NMe.sub.2                                                                              /  320-322                                       86 6-F  H   PhCH.sub.2                                                                            NHMe     /  271-273                                       87 6-F  H   PhCH.sub.2                                                                            NHMe     // >300                                          88 H    H   PhCH.sub.2                                                                            NMe.sub.2                                                                              // 268-269                                       89 6-F  H   Me      NMe.sub.2                                                                              // >300                                          90 6-F  H   iPr     NMe.sub.2                                                                              // 284-285                                       91 6-Cl H   PhCH.sub.2                                                                            NMe.sub.2                                                                              // >300                                          92 6-MeO                                                                              H   PhCH.sub.2                                                                            NMe.sub.2                                                                              // >300                                          93 6-Me H   PhCH.sub.2                                                                            NMe.sub.2                                                                              // 267 268                                       94 6-F  H   Ph      NMe.sub.2                                                                              // 295-297 d                                     95 6-F  H   Ph      NMe.sub.2                                                                              /  300 d                                         96 6-F  H   2-Thienyl-CH.sub.2                                                                    NMe.sub.2                                                                              // 318-320                                       97 H    Me  Ph      NMe.sub.2                                                                              /  196-197                                       98 6-F  Me  Ph      Pyrrolid // 203-205                                       99 6 F  Me  3-Thienyl-CH.sub.2                                                                    NMe.sub.2                                                                              /  196-197                                       100                                                                              6-F  Me  3 Thienyl-CH.sub.2                                                                    NMe.sub.2                                                                              // 172-174                                       101                                                                              6-F  Me  Ph      NMe.sub.2                                                                              // 195 197                                       102                                                                              6-F  Me  Ph      NMe.sub.2                                                                              /  213-215                                       103                                                                              6-F  Et  Ph      NMe.sub.2                                                                              // 210-212                                       104                                                                              6-F  Me  2-F--Ph NMe.sub.2                                                                              // 235-237                                       105                                                                              6-F  Me  4-F--Ph NMe.sub.2                                                                              // 214-215                                       106                                                                              6-Cl Me  Ph      NMe.sub.2                                                                              // 195-196                                       107                                                                              6-F  Me  4-Me--Ph                                                                              NMe.sub.2                                                                              // 252-254                                       108                                                                              6-Me Me  Ph      NMe.sub.2                                                                              // 192-193                                       109                                                                              H    Me  Ph      NMe.sub.2                                                                              // 205-207                                       110                                                                              6 F  Me  Ph      NHCH.sub.2 Ph                                                                          // 243-244                                       111                                                                              6-F  Me  Ph      NHMe     // 294-296                                       112                                                                              6-F  Me  3-F--Ph NMe.sub.2                                                                              // 199-202                                       113                                                                              6-F  Me  3-Cl--Ph                                                                              NMe.sub.2                                                                              // 186-188                                       114                                                                              6-F  Me  3-MeO--Ph                                                                             NMe.sub.2                                                                              // 215                                           115                                                                              6-F  Me  Ph      Morph    // 254-255                                       116                                                                              6-F  Me  Ph      4 Me-piperaz                                                                           // 224-226                                       117                                                                              6 F  Me  Ph      Piperid  // 178-180                                       118                                                                              6 F  Me  Ph      NEt.sub.2                                                                              // 164 165                                       119                                                                              6-F  Me  Ph      N(Me)(CH.sub.2).sub.2 OMe                                                              // 172-174                                       120                                                                              6-F  Me  Ph      3-HO-pyrrolid                                                                          // 201-202                                       121                                                                              6-F  Me  Ph      3-EtO-pyrrolid                                                                         // 189-190                                       122                                                                              6-F  Me  2-Pyridyl                                                                             NMe.sub.2                                                                              // 220-221                                       123                                                                              6-F  Me  Ph      N(Me)Et  // 181-182                                       124                                                                              6-F  Me  Ph      Pyrrolid // 203-205                                       125                                                                              6-F  Me  5-Me-thiadiaz                                                                         Pyrrolid // 299-301                                       126                                                                              6-F  Et  Ph      Pyrrolid // 172-174                                       127                                                                              6 Cl Me  Ph      Pyrrolid // 209-210                                       128                                                                              6-F  Me  5-Me-oxazol                                                                           Pyrrolid // 248-250                                       129                                                                              6-F  Me  Ph      Azetid   // 230-231                                       130                                                                              6-F  Me  Ph      N(Me)Pr  // 172-173                                       131                                                                              6-F  PhCH.sub.2                                                                        Ph      NMe.sub.2                                                                              // 201-203                                       132                                                                              6-F  Me  Ph      N(Me)CH.sub.2 Ph                                                                       // 148-149                                       133                                                                              6-F  cPrCH.sub.2                                                                       Ph      NMe.sub.2                                                                              // 178-179                                       134                                                                              6-F  Me  1-Napht NMe.sub.2                                                                              // 245-247                                       135                                                                              6 F  Me  2-Napht NMe.sub.2                                                                              // 185-186                                       136                                                                              6-F  Me  Ph      (S)-2-MeOCH.sub.2 --                                                                   //  96-107                                                           pyrrolid                                                  137                                                                              6-F  Me  Ph      N(Me)CH.sub.2 CH.sub.2 Ph                                                              // 174-176                                       138                                                                              6-F  Me  Ph      N(Me)CH.sub.2 CO.sub.2 Et                                                              // 158-160                                       139                                                                              6-F  Me  Ph      2-MeOCO--                                                                              // 115-118                                                           pyrrolid                                                  140                                                                              6-F  Me  Ph      N(Me)CH.sub.2 CH.sub.2 Ph                                                              // 151-153                                       141                                                                              6-F  Me  Ph      Thiazolid                                                                              // 187-188                                       142                                                                              6-MeO                                                                              Me  Ph      Pyrrolid // 258-259                                       143                                                                              6 F  Et  Ph      N(Me)Et  // 174-175                                       144                                                                              6-OCH.sub.2 Ph                                                                     Me  Ph      Pyrrolid // 199-201                                       145                                                                              6-CF.sub.3                                                                         Me  Ph      Pyrrolid // 211-212                                       146                                                                              6-F  H   Ph      Pyrrolid // 283-285                                       147                                                                              6-F  Me  Ph      NH(CH.sub.2).sub.4 OH                                                                  // 210-213                                       148                                                                              6-F  Me  Ph      NH(CH.sub.2).sub.3 CO.sub.2 H                                                          // 278-279                                       149                                                                              6-F  Me  Ph      NH(CH.sub.2).sub.3 CO.sub.2 Me                                                         // 154-156                                       __________________________________________________________________________     Key                                                                           Me denotes a methyl group, Et denotes an ethyl group, Pr denotes a propyl     group, iPr denotes an isopropyl group, cPr denotes a cyclopropyl group, P     denotes a phenyl group, 1Napht and 2Napht respectively denote naphth1-yl      and naphth2-yl groups, xPyridyl denotes a pyridinx-yl group, xThienyl         denotes a thienx-yl group, Piperid denotes a piperidin1-yl group, Pyrroli     denotes a pyrrolidin1-yl group, Morph denotes a  # morpholin4-yl group,       Azetid denotes an azetidin1-yl group, 4Me-piperaz denotes a                   4methylpiperazin-1-yl group, 5Me-thiadiaz denotes a                           5methyl-1,3,4-thiadiazol-2-yl group, 5Me-oxazol denotes a                     5methyl-1,2-oxazol-2-yl group, and Thiazolid denotes a thiazolidinyl          group.                                                                        In the column "3 ˜ 4", "/" denotes a carboncarbon single bond and       "//" denotes a carboncarbon double bond between the 3 and 4 atoms of the      molecule.                                                                     In the "M.p. (° C.)" column, "d" denotes a melting point with          decomposition.                                                           

The compounds of the invention were subjected to pharmacological testswhich demonstrated their advantage as substances having therapeuticactivities.

Study of Membrane Binding with Respect to ω₁ (Type 1 Benzodiazepine) andω₂ (type 2 benzodiazepine) receptors.

The affinity of the compounds for the ω₁ receptors of the cerebellum andω₂ receptors of the spinal cord was determined according to a variant ofthe method described by S. Z. Langer and S. Arbilla in Fund. Cdin.Pharmacol., 2, 159-170 (1988), with the use of [³ H]flumazenil insteadof [³ H]diazepam as radioligand.

The cerebellar or spinal cord tissue is homogenized for 60 s in 120 or30 volumes, respectively, of ice-cold buffer (50 mM Tris-HCl, pH 7.4,120 mM NaCl, 5 mM KCl) and then, after dilution to 1/3, the suspensionis incubated with [³ H]flumazenil (specific activity 78 Ci/mmol, NewEngland Nuclear) at a concentration of 1 nM and with the compounds ofthe invention at different concentrations, in a final volume of 525 μl.After 30 minutes of incubation at 0° C., the samples are filtered underreduced pressure on Whatman GF/B® filters and washed immediately withice-cold buffer.

The specific binding of [³ H]flumazenil is determined in the presence of1 μM unlabelled diazepam. The data are analysed according to standardmethods and the IC₅₀ concentration, the concentration which inhibits by50% the binding of [³ H]flumazenil, is calculated.

The IC₅₀ values of the most active compounds of the invention lie, inthis test, between 10 and 1000 nM.

Study of the Anxiolvtic Activity: Drink Intake Conflict Test.

The anxiolytic activity is evaluated in rats in the drink intakeconflict test according to the method described by J. R. Vogel, B. Beerand D. E. Clody in Psychopharmacologia (Berl.), 21, 1-7 (1971). Afterbeing deprived of water for 48 h, the rat is placed in a soundproofchamber equipped with a water pipette connected to an anxiometer whichdelivers a mild electric shock every 20 licks. The number of shocksreceived is automatically counted over 3 minutes and makes it possibleto evaluate the anxiolytic activity of the tested compounds. The resultsare expressed by the minimum effective dose (MED), the dose whichproduces a significant increase in the number of shocks received, withrespect to the number observed in the control animals.

The MED values of the most active compounds lie, in this test, between 5and 50 mg/kg via the intraperitoneal route.

Studs of the Anxiolvtic Activity: Test in a Heightened Cross-shaped Maze

The protocol of this test is a modification of that described by S.Pellow and S. File in Pharmacol. Biochem. Behav. (1986), 24, 525-529.After a period of accustomization to the experimental room lastingapproximately 24 h, the rats are placed individually on the centralplatform, the muzzle directed towards one of the closed arms, andobserved for 4 min using a video camera. The time spent by the animal inthe open arms, the number of entries into the closed arms and into theopen arms, the number of attempts to enter the open arms, followed by anavoidance response, and the exploration of the edges in the open armsare recorded. The results are expressed for each animal: 1) aspercentage of passages into the open arms relative to the total numberof entries into the four arms of the apparatus, 2) as percentage of timespent in the open arms relative to the total duration of the test (4min), 3) as total number of abortive attempts made by the animal, 4) astotal number of explorations.

The products under study are administered intraperitoneally or orally atincreasing doses. The results are expressed by the minimum effectivedose (MED) which produces either a significant increase (activity in theopen arms) or a significant decrease (attempts) relative to theperformance observed in the control animals.

The MED values of the most active compounds lie, in this test, between 3and 50 mg/kg via the intraperitoneal or oral route.

Study of the Hypnotic Activity.

The sedative or hypnotic activity of the compounds was determined byobserving their action on the rat's electrocorticogram, according to themethod described by H. Depoortere, Rev. E. E. G. Neurophysiol., 10, 3,207-214 (1980) and by H. Depoortere and M. Decobert, J. Phaxmacol.,(Paris), 14, 2, 195-265 (1983).

The products under study were administered intraperitoneally atincreasing doses. They induce sleep patterns at doses ranging from 1 to30 mg/kg.

Study of the Anticonvulsant Activity: Activity with Respect to ClonicConvulsions Induced in Rats by Injection of Pentetrazol.

The protocol of this test is a modification of that described by E. A.Swinyard and J. H. Woodhead in Antiepileptic Drugs, Raven Press, NewYork, 111-126 (1982).

The test products are administered to the animals intraperitoneally 30min before an intravenous injection of 20 mg/kg of pentetrazol.Immediately after the injection, the number of animals exhibiting clonicconvulsions is noted over 5 min.

The results are expressed as the AD₅₀, the dose which protects 50% ofthe animals, calculated according to the method of J. T. Lichtfield andF. Wilcoxon (J. Pharm. Exp. Ther. (1949), 96, 99-113) on the basis of 3or 4 doses each administered to a group of 8 to 10 rats.

The AD₅₀ values of the most active compounds lie between 0.3 and 30mg/kg via the intraperitoneal or oral route.

Study of the Anticonvulsant Activity: Activity with Respect toIsoniazid-induced Convulsions in Mice.

The intrinsic activity of the compounds is determined by the latencytime of onset of convulsions induced by the subcutaneous administrationof isoniazid (800 mg/kg) simultaneously with the test compound injectedintraperitoneally, according to the protocol described by G. Perrault,E. Morel, D. Sanger and B. Zivkovic in Eur. J. Pharmacol., 156, 189-196(1988) The results are expressed as the AD₅₀, the dose which produces50% of the maximum effect, relative to the control animals, determinedon the basis of 3 or 4 doses each administered to a group of 8 to 10mice. The AD₅₀ values of the compounds of the invention lie, in thistest, between 1 and 50 mg/kg via the intraperitoneal route and,depending on the compounds, the maximum effect can be as much as 300%.

The results of the tests performed on the compounds of the inventionshow that, in vitro, they displace [³ H]flumazenil from its specificbinding sites in the cerebellum and the spinal cord; they exhibit amixed affinity for the ω₁ and ω₂ (type 1 and type 2 benzodiazepine)sites situated in the GAB_(A) --ω sites--chlorine channel macromolecularcomplex.

In vivo, they behave as full or partial agonists with respect to thesereceptors.

They possess anxiolytic, hypnotic and anticonvulsant properties, and canconsequently be used for the treatment of complaints associated withdisorders of GABAergic transmission, such as anxiety, sleep disorders,epilepsy, spasticity, muscle contractures, cognitive disorders,withdrawal disorders related to alcoholism, tobacco or drugs, and thelike.

They can also be used for the treatment of Parkinson's disease and alltypes of extrapyramidal syndromes. Finally, they can be used inpremedication and as general anaesthetics for the induction and/ormaintenance of anaesthesia, or as local anaesthetics, optionally incombination with other anaesthetics and/or muscle relaxants and/oranalgesics.

To this end, they may be presented in any pharmaceutical dosage form, incombination with suitable excipients, for enteral or parenteraladministration, for example in the form of tablets, dragees, capsulesincluding hard gelatin capsules, solutions or suspensions to beswallowed or injected, suppositories, and the like, containing a dose topermit a daily administration of 1 to 1000 mg of active substance.

We claim:
 1. A compound having general formula (I) ##STR7## in which Xrepresents a hydrogen or halogen atom or a (C₁ -C₃)alkyl, (C₁-C₃)alkoxy, trifluoromethyl or phenylmethoxy group,R₁ represents ahydrogen atom or a (C₁ -C₃)alkyl, cyclopropyl or phenylmethyl group, R₂represents either a (C₁ -C₃)alkyl group optionally substituted by amethoxy group, or a phenyl(C₁ -C₃)alkyl group optionally substituted onthe phenyl ring by a halogen atom or a methyl or methoxy group, or acyclohexylmethyl group, or a thienylmethyl group, or a pyridinylmethylgroup, or a phenyl group optionally substituted by one or more halogenatoms or a (C₁ -C₃)alkyl or (C₁ -C₃)alkoxy group, or a pyridinyl group,or a 5-methyl-1,2-oxazolyl group, or a 5-methyl-1,3,4-thiadiazolylgroup, or a naphthyl group, R₃ and R₄, independently of one another,each represent a hydrogen atom, a (C₁ -C₃)alkyl group, a 2-methoxyethylgroup, a hydroxy(C₂ -C₄) alkyl group, a carboxy-(C₁ -C₃)alkyl group, a(C₁ -C₃)alkoxycarbonyl(C₁ -C₃)alkyl group or a phenyl(C₁ -C₃)alkylgroup, or else together form, with the nitrogen atom which carries them,either a pyrrolidinyl group optionally substituted by a hydroxyl,ethoxy, methoxycarbonyl or methoxymethyl group, or a piperidinyl group,or a morpholinyl group, or a 4-methylpiperazinyl group, or an azetidinylgroup, or a thiazolidinyl group, and the bond between the carbon atomsin the 3 and 4 positions is single or double.
 2. A compound according toclaim 1, wherein, X is in the 6 position and represents a fluorine atom.3. A compound according to claim 1, wherein R₁ represents a methylgroup.
 4. A compound according to claim 1, wherein R₂ represents aphenyl group.
 5. A compound according to claim 1, wherein R₃ representsa methyl group and R₄ represents an ethyl group.
 6. A compound accordingto claim 1, wherein R₃ and R₄ form, with the nitrogen atom which carriesthem, a pyrrolidinyl ring.
 7. A compound according to claim 1, whereinthe compound is in the form of a pure optical isomer.
 8. A compoundaccording to claim 1, wherein the compound is in the form of a mixtureof optical isomers.
 9. A pharmaceutical composition, comprising acompound according to one of claims 1 to 6, in combination with anexcipient.
 10. A process for the preparation of a compound according toclaim 1, which comprises:(a) reacting a compound of general formula (II)##STR8## in which X and R₁ are as defined in claim 1 and R represents a(C₁ -C₃)alkyl group, with ethyl pyruvate, to obtain a diester of generalformula (IV) ##STR9## (b) treating said diester with an amine of generalformula R₂ NH₂, in which R₂ is as defined in claim 1, to obtain an esterof general formula (V) ##STR10## (c) converting said ester by hydrolysisto a corresponding acid, of general formula (VI) ##STR11## and (d)converting said acid, by reaction with an amine of general formula HNR₃R₄, in which R₃ and R₄ are as defined in claim 1, either through animidazolide obtained by reaction with N,N-carbonyldiimidazole or throughan acid chloride, to a primary, secondary or tertiary amide of generalformula (I') ##STR12##
 11. A process as claimed in claim 10, whichfurther comprises oxidizing said primary, secondary or tertiary amide ofgeneral formula (I') by means of2,3-dichloro-5,6-dicyanocyclohexa-2,5-diene-1,4-dione or of3,4,5,6-tetrachlorocylohexa-3,5-diene-1,2-dione to obtain acorresponding compound of general formula (I")
 12. A process for thepreparation of a compound according to claim 1, which comprises: (a)reacting a compound of general formula (VII) ##STR13## in which X is asdefined in claim 1, with 2-ketoglutaric acid; (b) treating the productof step (a) in an acidic alcoholic medium to obtain a diester of generalformula (IX) ##STR14## in which R represents a (C₁ -C₃)alkyl group; (c)alkylating the diester of formula (IX) to obtain a compound of generalformula (X) ##STR15## in which R₁ represents a (C₁ -C₃)alkyl group; (d)converting said compound of general formula (X), in the presence ofdimethylformamide dimethyl acetal, into a compound of general formula(XI) ##STR16## in which R₁ represents a methyl group; (e) treating saidcompound of general formula (XI) with an amine of general formula H₂NR₂, in which R₂ is as defined in claim 1, to obtain an ester of generalformula (V') ##STR17## (f) converting said ester to a corresponding acidof general formula (VI') ##STR18## and (g) converting said acid to aprimary, secondary or tertiary amide of general formula (I") ##STR19##either through an imidazolide obtained by reaction withN,N'-carbonyldiimidazole or through an acid chloride.
 13. A process forthe preparation of a compound according to claim 1, which comprises:(a)reacting a compound of general formula (VIII) ##STR20## in which X is asdefined in claim 1, with 2-ketoglutaric acid; (b) treating the productof step (a) in an acidic alcoholic medium to obtain a diester of generalformula (IX) ##STR21## in which R represents a (C₁ -C₃)alkyl group; (c)converting said diester of formula (IX) directly into a compound ofgeneral formula (XI) ##STR22## in which R₁ represents a methyl group;(d) treating said compound of general formula (XI) with an amine ofgeneral formula H₂ NR₂, in which R₂ is as defined in claim 1, to obtainan ester of general formula (V') ##STR23## (e) converting said ester toa corresponding acid of general formula (VI') ##STR24## and (f)converting said acid to a primary, secondary or tertiary amide ofgeneral formula (I") ##STR25## either through an imidazolide obtained byreaction with N,N'-carbonyldiimidazole or through an acid chloride. 14.A process for the preparation of a compound according to claim 1, whichcomprises:(a) hydrolyzing a diester of general formula (X) ##STR26## inwhich X and R₁ are as described in claim 1, to obtain a diacid ofgeneral formula (XII) ##STR27## (b) converting said diacid to ananhydride, to obtain a compound ##STR28## of the general formula (XIII)(c) reacting said anhydride with an amine of general formula HNR₃ R₄, inwhich R₃ and R₄ are as defined in claim 1, to obtain a compound ofgeneral formula (XIV) ##STR29## (d) converting said compound of generalformula (XIV) to an ester of general formula (XV) ##STR30## (e) treatingsaid ester in the presence of dimethylformamide dimethyl acetal, toobtain a compound of general formula (XVI) ##STR31## and (f) reactingsaid compound of general formula (XVI) with an amine of general formulaR₂ NH₂, in which R₂ is as defined in claim 1, to obtain a compound ofgeneral formula (I") ##STR32##
 15. A process as claimed in claim 14,further comprising, when the compound of general formula (I") is asecondary amide, converting said secondary amide to a tertiary amide byan alkylation reaction.